Beyond the "First Hit": Marked Inhibition by N‐Acetyl Cysteine of Chronic Ethanol Intake But Not of Early Ethanol Intake. Parallel Effects on Ethanol‐Induced Saccharin Motivation. (8th April 2016)

• Record Type: Journal Article
• Authors: Quintanilla, María Elena; Rivera‐Meza, Mario; Berríos‐Cárcamo, Pablo; Salinas‐Luypaert, Catalina; Herrera‐Marschitz, Mario; Israel, Yedy
• Is Part Of: Alcoholism. Volume 40:Number 5(2016)
• Page Start: 1044
• Page End: 1051
• Publication Date: 2016-04-08
• Subjects: Voluntary Ethanol Drinking -- N‐Acetyl Cysteine Saccharin -- Acquisition -- Maintenance; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.13031
• Languages: English
• ISSNs: 0145-6008

Abstract

Abstract : Background: A number of studies have shown that acetaldehyde synthesized in the brain is necessary to induce ethanol (EtOH) reinforcement in naïve animals ( acquisition phase ). However, after chronic intake is achieved ( maintenance phase ), EtOH intake becomes independent of acetaldehyde generation or its levels. Glutamate has been reported to be associated with the maintenance of chronic EtOH intake. The levels of brain extracellular glutamate are modulated by 2 glial processes: glutamate reabsorption via an Na + ‐glutamate transporter (GLT1) and a cystine–glutamate exchanger. Chronic EtOH intake lowers GLT1 levels and increases extracellular glutamate. The administration of N ‐acetyl cysteine (NAC), a precursor of cystine, has been shown to reduce the relapse of several drugs of abuse, while NAC has not been tested on chronic EtOH intake or on EtOH's influence on the motivation for another drug. These were investigated in the present study. Methods: (i) Rats bred for their high EtOH intake were allowed access to 10% EtOH and water up to 87 days. NAC was administered (30 and 60 mg/kg daily, intraperitoneally) for 14 consecutive days, either during the acquisition phase or the maintenance phase of EtOH drinking. (ii) In additional experiments, rats were allowed EtOH (10%) and water access for 61 days, after which EtOH was replaced by saccharin (0.3%) to determine both if chronic EtOH consumption influences saccharin intake and whether NAC modifies the post chronic EtOH saccharin intake. Results: NAC did not influence the acquisition ("first hit") of chronic EtOH intake, but greatly inhibited (60 to 70%; p < 0.0001) EtOH intake when NAC was administered to animals that were consuming EtOH chronically . NAC did not influence saccharin intake in naïve animals. In animals that had consumed EtOH chronically and were thereafter offered a saccharin solution (0.3%), saccharin intake increased over 100% versus that of EtOH‐untreated animals, an effect that was fully suppressed by NAC. Conclusions: N ‐acetyl cysteine, a drug approved for use in humans, markedly reduces chronic EtOH intake and abolishes the increased intake of saccharin stimulated by chronic EtOH drinking. Abstract : The early brain mechanisms that lead to self‐administration ( initiation ) of most addictive drugs invoke different neuronal elements, while the mechanisms that perpetuate their consumption ( maintenance ) share some common processes. In rats that were consuming ethanol chronically, the administration of N ‐acetyl cysteine (NAC, shaded in the figure)—a drug known to reduce cocaine relapse in humans—markedly lowers the maintenance of alcohol intake. This study suggests that several drug use disorders might benefit from N ‐acetyl cysteine treatment.